Derivative of tropic acid amide



Patented May 2, 1944 UNITED STATES PATENT OFFICE 1 2,347,721 DERIVATIVE F TROPIC ACID AmDE Wilhelm Wenner, Montclair, N.

Hoffmann-La Roche Inc., Nutiey,

poration of New Jersey No Drawing.

.L, assignor to N. J., a cor- Original application June 26, 1939,

Serial No. 281,269. Divided and this application October 14, 1942, Serial No. 462,063.

Germany July 7, 4 Claims. (Cl. 260-559) The need for an effective choleretic has become more and more evident in recent years since it has been established that by increasing the secretion of bile, illnesses of the liver and bile ducts can be favorably influenced. A number of cholagogic preparations have in fact already been placed on the market. The better known amon them contain as active substances bile acid derivatives, podophyllin, as well as extracts from plants (e. g. radish extract). Extracts from liver and gall bladder have also been employed as choleretics.

It has now been found that tropic acid amide and its neutral N-substituted derivatives possess a strong cholagogic action.

Only tropic acid amide has been described in the literature up to the present, (Annalen der Chemie, vol. 389, year 1912, pagelll). This was obtained through the following intermediate stages: Tropic acid, atropic acid, fi-bromo-aphenyl propionic acid. The manufacture of atropic acid as well as of fl-bl'OIHO-a-PhBIlYl-PTO- pionic acid does not proceed satisfactorily because the formation of by-produ-cts cannot be avoided (Annalen der Chemie, vol. 209, year 1881, page 12., paragraph 4). Likewise, the transformation of B- bromo-a-phenyl propionic acid into tropic acid amide can only be carried out in poor yield, since atropic acid as well as atrolactio acid and styrol occur as icy-products (Annalen der Chemie, vol. 115, year 1860, page 159; vol. 209, year 1881, page 11) This process cannot therefore be taken into 7 consideration for the technical synthesis of tropic acid amide.

The disadvantages descr'bed can be avoided if tropic acid amide is obtained by allowingammonia to act on o-acetyl tropic acid chloride. The ammonia may be employed in aqueous solution or in a suitable organic solvent, such as benzene, toluene, ether, chloroform, petroleum ether. o-Acetyl tropic acid amide is obtained in very good yield. By treating this compound with acids or alkalis under suitable conditions, the acetyl group is split off.

If amines, e. g., aliphatic primary and secondary amines, cycloalkyl amines, are caused to act on o-acetyl tropic acid chloride in the same manner, the corresponding substituted amides of o-acetyl tropic acid are obtained. The amines employed are also best used in solution in water or in an organic solvent. The acetyl group is split off by treatment with alkalis or acids from the resulting o-acetyl tropic acid amides substituted in the amido group.

Tropic acid amide and its neutral N-substituted derivatives are colorless compounds. The lower members of the series are crystalline, the higher members mostly liquids. They are to be employed as choleretics. The examination of the cholagogic action was carried out in accordance with Grabes process (Archiv fiir experimentelle Pathologie und Pharmakologie, vol, 176, year 1934, page 6'73). According to this method the gall secretion in the narcotised rat .is first determined over a period of 2 hours, the preparation to be examined then administered by means of a stomach tube, and the ensuing change in the gall secretion observed.

The comparison of tropic acid dimethyl amide with desoxycholic acid, whose choleretic action is described in the literature (Biochemische Zeitschrift, vol. 130, year 1922, page 556; Zeitschrift fiir die gesamte experimentelle Medizin, vol. 30, year 1922, page 423) clearly shows the superiority of the new class of compounds.

Number of drops of bile per hour- Preparation g? Dosc cent of Before ap- After application of plication of preparation preparation MgJlcg. Tropic acid 1 50 8 l3 dimethyl 2 50 l2 l5 amide. 3 50 l2 l6 4 50 17 22 5 50 18 27 6 5O 18 32 7 50 14 26 8 5t) 16 42 9 25 l0 18 10 25 18 23 ll 25 13 9 12 25 16 23 Desoxycholic 13 50 15 12 acid. 14 50 l5 12 15 50 9 ll 16 50 15 19 17 25 9 8 18 25 9 l0 19 ll 6 20 25 19 1 Example 1 45 parts by weight of o-acetyl tropic acid chloride are added dropwise to 56 parts by weight of aqueous ethylamine solution (33 per cent) while stirring, the temperature being kept at 20-30 C. The reaction mixture is extracted with benzene. After evaporation of the benzene, about 35 parts by weight of crude o-acetyl tropic acid ethylamide are obtained. By short heating with a dilute solution of caustic soda the acetyl group is split off and tropic acid ethylamide of meltin point 129 c; is obtained. per cent of the theoretical.

If allylamine is used instead of ethylamine, the

above reaction produces tropic acid allyl amide melting at 140 C.

The yield is about 80 V Example 2 45 parts by weight of o-acetyl tropic acid chloride are added drop by drop to 55 parts by Weight dimethyl amide melting at 96 C. are obtained.

Example 3 temperature for 2 days. The mixture is then neutralized and evaporated to dryness. Tropic acid diethylamide of melting point 84 C. is obtained. V o

parts by weight of tropic acid Example 4 45 parts by weight of o-acetyl tropic acid chloride are dissolved in 120 parts by weight of a solution of 52 of di-n-butylamine in 350 parts 1. A derivative of tropic acid amide of the Q formula wherein R. is selected from the group consisting of hydrogen and a lower alkyl and R" is a. lower alkyl.

2. Tropic acid mono-ethylamide.

3. Tropic acid dimethylamide.

4. Tropic acid diethylamide.

WILHELM WENNER. 

